Mounting evidence suggests that the symptoms associated with some cases of autism may result from a genetically-determined immune deficiency and/or an autoimmune mechanism. Circumstantial evidence for this hypothesis stems from the number of features that autism shares with established immune deficiencies and autoimmune disorders including: genetic predisposition, general immune imbalances, association with the HLA or the major hitocompatibillity complex (MHC) on chromosome 6, association with viral and other infections, demonstration of cell-mediated immunity and serum antibodies against proteins of the central nervous system, and an uneven sex distribution (autism is 4-5 times more frequent in boys than in girls). The investigator's laboratory has made several findings during the initial and first renewal periods of this project providing additional evidence for the immunodeficiency-autoimmune hypothesis for some cases of autism. These include an association of the MHC with autism including an increased frequency of the C4B null allele with the resultant reduced plasma levels and reduced C4 function, supporting the concept of immune susceptibility to a microorganism or a pathogen. The investigators have also found an elevated representation of the extended MHC haplotype B44-SC30-DR4. The MHC was associated with a stronger history of infections in the autistic patients. Some of the autistic subjects demonstrated decreased levels of immunoglobulin A which also appeared to be associated with a gene within the MHC. Finally, the investigators have observed DR+ (activated) T cells in some of the patients (which confirmed an earlier finding by another laboratory) and an altered T cell receptor (TRC) Vbeta profile including increased frequencies of the Vbetas 8.1, 8.2 and 13. The DR4 (DRb1*0401) portion of the extended haplotype b44-SC30-DR4 shares a common amino acid sequence motif in the third hypervariable region (HVR-3) with several other extended haplotypes. This shared motif, seen in more than 50% of the autistic subjects, provides a plausible explanation for the possible existence of immune deficiency or autoimmune-disease in some autistic subjects. This renewal project will: 1) investigate association of the MHC with autistic subjects located in an area other than northern Utah; 2) study, using molecular genetic technology, whether another gene, within the extended haplotype in proximity to the C4B gene of the MHC, rather than the C4B gene itself, is primarily associated with autism; 3) explore evidence for and against the possibility that immune deficiency is related to autism by allowing a pathogen or microorganism to persist and damage the brain or interfere with normal brain function; and 4) determine whether or not autoimmune processes are associated with the development of autism. These studies may lead to a new treatment approach for autism.